Utility of Matrix Metalloproteinases in the Diagnosis, Monitoring and Prognosis of Ovarian Cancer Patients

Figures & data

Table 1 FIGO’s Staging Classification for Ovarian Cancer

Stage I: Tumor confined to ovaries or fallopian tube(s)

Stage II: Tumor involves one or both ovaries or fallopian tubes with pelvic extension (below pelvic brim) or peritoneal cancer

Stage III: Tumor involves 1 or both ovaries or fallopian tubes, or peritoneal cancer, with cytologically or histologically confirmed spread to the peritoneum outside the pelvis and/or metastasis to the retroperitoneal lymph nodes

Stage IV: Distant metastasis excluding peritoneal metastases

Note: Data adapted from Javadi et al,²¹ Prat et al,²⁷ and Berek et al.²⁸

Figure 1 Symptoms and complications of ovarian cancer and the most common sites of metastatic foci.

Figure 2 Division of matrix metalloproteinases.

Abbreviations: MMP-1, Metalloproteinase-1; MMP-2, Metalloproteinase-2; MMP-3, Metalloproteinase-3; MMP-7, Metalloproteinase-7; MMP-8, Metalloproteinase-8; MMP-9, Metalloproteinase-9; MMP-10, Metalloproteinase-10; MMP-11, Metalloproteinase-11; MMP-12, Metalloproteinase-12;MMP-13, Metalloproteinase-13; MMP-14, Metalloproteinase-14; MMP-15, Metalloproteinase-15; MMP-16, Metalloproteinase-16; MMP-17, Metalloproteinase-17; MMP-18, Metalloproteinase-18; MMP-19, Metalloproteinase-19; MMP-20, Metalloproteinase-20; MMP-21, Metalloproteinase-21; MMP-24, Metalloproteinase-24; MMP-25, Metalloproteinase-25; MMP-26, Metalloproteinase-26; MMPs, Matrix metalloproteinases.

Figure 3 Multidirectional role of MMPs in carcinogenesis.

Table 2 The Most Significant Properties of MMPs Groups Found in Tissue Studies and Body Fluids

Gelatinases
MMP	Results	References
MMP-2	Research in tissues -Expression was found in: physiological ovarian tissue, all histological types of OC samples, in cancer epithelial cells, stroma cells and metastatic foci -Conflicting data on expression differences between different OC histological types - Single studies show higher expression in serous ovarian carcinoma type and chemotherapy-sensitive OC -Expression independent from disease stage, tumor size and treatment effects - Expression dependent from OC tendency to recur and metastasis -The relationship between expression in cancer epithelial cells and prognosis is contradictory. It is observed: a) Worse prognosis of patients with higher MMP-2 expression or b) No relationship between expression and prognosis of patients -The relationship between expression in stroma cells and prognosis is contradictory. It is observed: a) Shorter or b) Longer survival time of patients with higher MMP-2 expression	[14–16,139,141–148,152]
	Research in body fluids -Serum levels lowers in OC patients than in healthy women -Serum concentrations independent from OC stage -No differences in serum concentrations between OC patients and women with benign lesions -Plasma concentrations independent from patient prognosis -Higher urine levels in OC patients with normal CA-125 blood levels	[152,155,160]
MMP-9	Research in tissues -Expression was found in: all histological types of OC samples, in cancer epithelial cells, stroma cells and metastatic foci -Expression in physiological ovarian tissue is low or undetectable -Conflicting data on expression differences between different OC histological types - Single study shows higher expression in high-grade serous OC -Higher expression in OC than in benign lesions -Higher expression in OC patients with present metastatic foci than in patients without metastatic foci -Expression dependent on OC stage (higher expression in more advanced stage), and number of vasculogenic-like networks -The relationship between expression in OC tissue and prognosis is contradictory. It is observed: a) Shorter or b) Longer survival time of patients with higher MMP-9 expression	[14,139–148]
	Research in body fluids -No correlation between serum concentrations and OC histological types -Serum and plasma concentrations higher in OC patients compared to healthy women and those with benign lesions -Serum concentrations higher in more advanced stage OC and in patients insensitive to chemotherapy and with ascites or metastatic foci - Plasma concentrations independent of patients prognosis -Decline in serum concentrations after surgery - Highest sensitivity values in assays with CA-125 in plasma - Higher urine levels in OC patients with normal CA-125 blood levels	[14,152,156–158,160]
Collagenases
MMP	Results	References
MMP-1	Research in tissues -Activity was found in physiological ovarian tissue -Expression was found in OC samples -Higher expression in OC than in benign lesions	[16,161,163–166]
	Research in body fluids -Low activity in ovarian cyst fluid -There was no difference between activity in the fluids from malignant and benign cysts	[164]
MMP-8	Research in tissues -Expression in physiological ovarian tissue and benign lesions has not been studied -Expression was found in OC samples -Expression dependent on OC stage (higher expression in more advanced stage - Higher expression was associated with worse prognosis -Higher expression was associated with higher MMP-9 expression	[16,164,165]
	Research in body fluids -Higher activity in malignant cyst fluids compared to benign cyst fluids	[164]
MMP-13	Research in tissues -Not expressed in physiological ovarian tissue -Expression in begin lesions has not been studied -Expression was found in OC samples -Expression independent from disease stage or whether cancer occupied one or two ovaries -Higher expression was associated with worse prognosis of patients	[16,164–166]
	Research in body fluids -Low activity in ovarian cyst fluid -Higher expression in peritoneal fluid was associated with worse prognosis of patients	[164,167]
MMP-18	Research in tissues -Expression was found in physiological ovarian tissue -Expression in OC tissue and benign lesions was not studied	[162]
Stromelysins
MMP	Results	References
MMP-3	Research in tissues -Expression was found in physiological ovarian tissue and in OC samples -Expression dependent on OC stage (higher expression in more advanced stage) -Expression independent from patients prognosis	[16,166,170–173]
	Research in body fluids -Serum concentrations higher in OC patients compared to women with benign lesions -Serum concentrations dependent on OC stage (higher concentration in more advanced stage) -High serum levels were associated with shorter progression-free time and worse overall survival	[174]
MMP-10	Research in tissues -Not expressed in physiological ovarian tissue -Expression was found in OC samples -High expression associated with better overall survival of patients in stage III and IV in accordance with FIGO	[16,166,171,172]
MMP-11	Research in tissues -Expression in physiological ovarian tissue has not been studied -Expression was found in OC samples -Higher expression was associated with higher expression of MMP-2 and MMP-13 -Expression dependent on OC stage (higher expression in more advanced stage) -Expression independent from patients prognosis	[16,166,171–173]
Matrilysins
MMP	Results	References
MMP-7	Research in tissues -Low expression in physiological ovarian tissue -Expression was found in: OC tissues, stroma cells, metastatic foci and in the mucin of mucinous ovarian carcinoma -Conflicting data on expression differences between OC and begin lesions. It is observed: a) Higher expression in serous OC compared to benign lesions or b) Higher expression in benign lesions compared to serous OC -Conflicting data on the relationship between expression and prognosis. It is observed: a) Better prognosis in patients with high expression of MMP-7 or b) Expression independent from patients prognosis -Low expression associated with advanced stage, high histological grade OC and large primary residual tumor	[16,117,143,144,166,175–177,179]
	Research in body fluids -Serum and plasma concentrations higher in OC patients compared to healthy women and begin lesions -No relationship between serum levels and tumor stage and grade, presence of metastasis or ascites -Positive correlation between serum concentrations and primary tumor size -Decrease in serum concentrations after surgery and chemotherapy -Parallel to CA-125 and HE4 values of diagnostic parameters (sensitivity, specificity, negative and positive predictive values) after determination from plasma	[155,179–181]
MMP-26	Research in tissues -High or low expression depending on the structure of the ovary -Expression was found in OC samples -Differences in expression between OC and benign lesions have not been studied -Expression dependent on OC stage (higher expression in stage III and IV compared to stage I) -No relationship between expression and prognosis of patients with OC	[16,155,166,178,179]
Membrane-type MMPs
MMP	Results	References
MMP-14	Tissue expression -Conflicting data on expression in physiological ovarian tissue. It is observed: a) Expression in physiological ovarian tissue or b) No expression in physiological ovarian tissue -Expression was found in: OC samples, in cancer epithelial cells and in stroma cells -Simultaneous expression in cancer epithelial cells and stroma associated with ascites and lymph node involvement -High expression in epithelial cells associated with the development of distant metastatic foci -High expression in OC tissue was associated with low CA-125 expression -Conflicting data on expression differences between OC and begin lesions. It is observed: a) higher expression in OC compared to benign lesions or b) No expression in benign lesions -Relationship between expression in cancer epithelial cells and stroma and prognosis different or contradictory. It is observed: a) High expression simultaneously in epithelium and stroma was associated with low disease-related survival rates, b) High expression only in epithelial cells was associated with the lowest disease-related survival rates, c) Moderate expression in cancer epithelial cells with concomitant low expression in stroma was associated with the best prognosis of patients and d) No correlation between expression and prognosis of patients.	[13,16,142,144,166,173,183–187,189]
	Research in body fluids -Serum concentrations higher in OC patients compared to healthy women and begin lesions	[190]
MMP-15	Tissue expression -Conflicting data on expression in physiological ovarian tissue. It is observed: a) Expression in physiological ovarian tissue or b) No expression in physiological ovarian tissue -Expression was found in OC samples -Expression independent from patients prognosis	[16,166,183–185]
MMP-16	Tissue expression -Conflicting data on expression in physiological ovarian tissue. It is observed: a) Expression in physiological ovarian tissue or b) No expression in physiological ovarian tissue -Expression was found in OC samples -Expression dependent on OC stage (higher expression in more advanced stage) -Expression independent from patients prognosis	[16,166,183–185,188]
MMP-17	Tissue expression -Conflicting data on expression in physiological ovarian tissue. It is observed: a) Expression in physiological ovarian tissue or b) No expression in physiological ovarian tissue -Expression was found in OC samples -Expression independent from OC stage -Expression independent from patients prognosis	[16,166,183–185]
MMP-24	Tissue expression -Conflicting data on expression in physiological ovarian tissue. It is observed: a) Expression in physiological ovarian tissue or b) No expression in physiological ovarian tissue -Expression was found in OC samples -Expression independent from OC stage -Expression independent from patients prognosis	[16,166,183–185]
MMP-25	Tissue expression -Conflicting data on expression in physiological ovarian tissue. It is observed: a) Expression in physiological ovarian tissue or b) No expression in physiological ovarian tissue -Expression was found in OC samples -Expression dependent on OC stage (higher expression in more advanced stage) -Higher expression was associated with longer overall survival	[16,166,183–185]
Other types of MMPs
MMP	Results	References
MMP-12	Tissue expression -Not expressed in physiological ovarian tissue -Expression was found in serous and endometrioid OC -Expression independent from OC stage -High expression in OC samples was associated with better overall survival (stage III or IV patients)	[16,166]
MMP-19	Tissue expression -Expression in physiological ovarian tissue has not been studied -Expression was found in serous and endometrioid OC -Expression independent from OC stage -The relationship between expression in OC samples and prognosis is contradictory. It is observed: a) High expression associated with poor overall survival or b) Expression independent from patients prognosis	[16,166]
MMP-20	Tissue expression -Expression in physiological ovarian tissue has not been studied -Expression was found in serous and endometrioid OC -Expression independent from OC stage -The relationship between expression in OC samples and prognosis is contradictory. It is observed: a) High expression associated with poor overall survival or b) Expression independent from patients prognosis	[16,166]
MMP-21	Tissue expression -Expression in physiological ovarian tissue has not been studied -Expression was found in serous and endometrioid OC -Expression independent from patients prognosis	[16,166]

Figure 4 Diagnostic potential of individual MMPs in ovarian cancer patients. *Conflicting data about respective MMPs were shown in separate studies.

Abbreviations: MMP-1, Metalloproteinase-1; MMP-2, Metalloproteinase-2; MMP-3, Metalloproteinase-3; MMP-7, Metalloproteinase-7; MMP-8, Metalloproteinase-8; MMP-9, Metalloproteinase-9; MMP-10, Metalloproteinase-10; MMP-11, Metalloproteinase-11; MMP-12, Metalloproteinase-12; MMP-13, Metalloproteinase-13; MMP-14, Metalloproteinase-14; MMP-15, Metalloproteinase-15; MMP-16, Metalloproteinase-16; MMP-17, Metalloproteinase-17; MMP-18, Metalloproteinase-18; MMP-19, Metalloproteinase-19; MMP-20, Metalloproteinase-20; MMP-21, Metalloproteinase-21; MMP-24, Metalloproteinase-24; MMP-25, Metalloproteinase-25; MMP-26, Metalloproteinase-26; MMPs, Matrix metalloproteinases.

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